PROJECT SUMMARY/ABSTRACT Major depressive disorder (MDD), a disease affecting up to 16% of the U.S. population at some point in their lives, has been likened to a state of ?accelerated aging,? with an increased risk of acquiring certain diseases of aging and of premature mortality. Evidence consistent with accelerated aging is reported in the brain as well as in the periphery in MDD. The biological mechanisms underlying this process are beginning to be understood, largely by studying immune cells with shortened telomeres, which is now reported in several studies of MDD. Telomeres cap and protect the cell's DNA, and when telomeres become critically short, cells may undergo apoptosis and die. The body protects telomeres by activating a cellular enzyme, telomerase. Telomerase also has important roles in cell survival, neurogenesis and, in animal models, intrinsic antidepressant effects. These latter effects may be mediated via actions in the hippocampus and other brain regions important in MDD. Our preliminary data suggest that telomerase activity (TA) is important in achieving antidepressant response, and that TA is correlated with volume of the hippocampus and anterior cingulate gyrus, both of which are implicated in MDD. A major Aim is to determine whether cell aging in peripheral cells bespeaks a more generalized process of accelerated cell aging in unmedicated individuals with MDD, focusing on the brain. In particular, we will determine whether peripheral aging markers (leukocyte telomere length [LTL] and TA) are significantly correlated with brain structural and biochemical abnormalities in MDD, as detected by neuroimaging (magnetic resonance imaging [MRI] and magnetic spectroscopic imaging [MRS]); the existence of such relationships would tie peripheral cell aging to neural abnormalities in MDD. Our neuroimaging focuses on the corticolimbic network, which is critical in MDD and which showed strong relationships with cell aging markers in our preliminary data. Our other major Aim is to determine whether the relationship between changes in depression ratings and in cell aging markers during antidepressant treatment is mediated by changes in MRS indices (N-acetyl aspartate, a marker of neuronal integrity, and choline-containing metabolites related to glial metabolism and membrane breakdown). To accomplish this, we will recruit 48 un- medicated individuals with MDD and assess LTL and TA, along with depression ratings and MRI and MRS. Depressed individuals will then be treated with an antidepressant for 8 weeks and baseline procedures will be repeated. We will determine the relationship between cell aging markers, MDD symptoms and corticolimbic network disturbances as well as between their changes with treatment. Controls will be assessed at baseline and 8 weeks to assess natural changes in measures over time. Accomplishing these Aims will aid in developing a new mechanistic understanding of the MDD pathophysiology, which would link neural pathology with the increased somatic illness incidence in MDD. It will also point to novel mechanism-based targets for treatment development, and will foster the development of blood-based biomarkers of MDD neural pathology.